Cutaneous T cell lymphomas (CTCL) are largely incurable and in advanced stage, profoundly debilitating. Mycosis Fungoides (MF), one of the most common subtypes of CTCL, may be effectively treated in early stage, but there is no curative therapy for advanced MF except for allogeneic stem cell transplantation (SCT) for which few patients are eligible. Response to therapy is usually partial and transient; patients frequently succumb to sepsis and other infections as a consequence of immune dysfunction and loss of barrier protection. Effective and innovative treatment strategies for MF, derived from an understanding of lymphoma biology are an ongoing unmet need. Dysregulation of the innate immune system is seen at all stages of MF, and underlies both disease morbidity and lymphomagenesis. Immune stimulatory therapies, have demonstrated anti-tumor effects, primarily in early stage and limited disease. The FDA approved first line of therapy for patients with advanced MF is epigenetic therapy, using histone deacetylase inhibitors (HDACI). The response rate to these agents is modest, (overall response rate of 30% and complete response rate < 10%). This may be a result of the suppression of cellular immune function induced by HDACI despite their anti-tumor properties, exacerbating the immunologic deficiency that creates a permissive niche for this lymphoma. Effective treatment platforms for advanced MF are needed that combine anti-tumor therapy with immune stimulation; however, to date this strategy has not been tested. Our group at NYU has previously demonstrated that focal lesion radiation can induce immune stimulation and out of field tumor shrinkage (an 'abscopal' response). We propose to treat advanced MF patients receiving epigenetic therapy with in situ vaccination, consisting of focal lesion radiation with or without a toll-like receptor (TLR) agonist, an additioal immune stimulant. We hypothesize that this intervention will be well-tolerated, and will induce systemic immune activation and clinical response. The specific aims of the proposed research are: 1) Evaluate in a phase 1 pilot study the safety and clinical activity of the addition of in siu vaccination with focal lesion radiation and a TLR3 agonist to epigenetic therapy with romidepsin, in patients with advanced MF, and 2) Determine whether this treatment platform augments tumor specific immunity, and induces a) an immune signature consistent with tumor rejection in the microenvironment, and b) evidence of systemic immune activation. If these hypotheses are validated, this will support a larger scale clinical trial. This research is innovative because itis the first study to propose augmenting the anti-tumor effects of epigenetic therapy with immune stimulation in MF, an immune mediated lymphoma. It is significant because this therapeutic approach may be applied to the treatment of other lymphomas and/or immune mediated malignancies. If validated, this strategy may significantly impact the morbidity and mortality of MF patients.